The Oncology Journal Club Podcast Episode 3: Immunotherapy, Microbiome, Sexual Health and Quality of Life Post-Treatment

The Oncology Journal Club - Delivering Oncology News Differently

The Oncology Podcast, part of The Oncology Network, is proud to present Episode 3 in the second series of The Oncology Journal Club Podcast.

Dr Kate Clarke explores a clinical conundrum with the latest insights on neo-adjuvant immunotherapy for DMMR, MSI-high GI cancers, discussed with the clarity and depth you've come to expect from our team. For Professor Craig Underhill's main paper segment, Dr. Ashray Gunjur drops by to discuss the microbiome's predictive power in immunotherapy responses, Professor Christopher Jackson delves into the OPRA study's latest findings on chemo-radiotherapy sequencing for rectal cancer, bringing to light the pivotal role of patient-centred discussions.

In Quick Bites, the discussion hits home with the three S's—sitting, shitting, and sex—and their profound impact on post-cancer quality of life. Highlighting the importance of comprehensive support systems in these often-overlooked areas, we also dissect the worrying trend of early-onset colorectal cancer and its broader implications. With a review of a study about the duration of immunotherapy in non-small cell lung cancer, this episode promises to fuel ongoing debates on treatment duration and patient outcomes, highlighting our commitment to keeping you at the forefront of oncology discourse.

The conversation takes a crucial turn as we tackle the uncomfortable yet necessary topic of presenting unfunded treatment options in oncology, exposing the delicate balance healthcare professionals must maintain in an era marked by scarce resources and rising demands.

For papers, bios and other links visit the Show Notes on our website.

For the latest oncology news visit www.oncologynews.com.au.

We invite healthcare professionals to join The Oncology Network for free - you'll also receive our free weekly publication The Oncology Newsletter.

The Oncology Podcast - An Australian Oncology Perspective

Transcript

Rachael Babin: 0:10

Hello, I'm Rachel Babin from the Oncology Podcast, part of the Oncology Network. Welcome to the Oncology Journal Club podcast, a trans-Tasman podcast offering expert analysis and discussion of the latest oncology papers. The listeners will be familiar with our format. The hosts present main papers or interviews with guests, alongside some quick-bite papers, thoughtful discussion and entertaining banter.

Rachael Babin: 0:40

Dr Kate Clarke gets us started with a paper she looked up to solve a clinical conundrum. It explores neo-adjuvant immunotherapy for patients with DMMR, msi-high GI cancers. We have highlights from our host Craig Underhill's separate the OJC meets interview with Ashray Gunjur about the microbiome's role in predicting patient response to immunotherapy, followed by insightful discussion from the team who advise you to ignore the microbiome at your peril. Professor Christopher Jackson talks us through the fascinating long-term results of organ preservation in patients with rectal adenocarcinoma. We have a wide-ranging selection of quick bites covering sexual health, h. pylori, re-challenge after hypersensitivity reactions and low-graded verse events. We also include an impassioned debate about resource allocation and treatment, de-intensification and the role of the oncologist in balancing new treatments and limited public health resources. Please see the show notes on oncologynetwork. com. au for papers, links and full bios of the host and guest speaker.

Rachael Babin: 1:49

We hope you enjoy listening. This is Rachel Babin and this is the Oncology Journal Club podcast.

Craig Underhill: 1:58

G'day Kia Ora, Kia Ora. It's a great pleasure to welcome back everybody to episode of three of Oncology Journal Club podcast across the ditch. Welcome Professor Chris Jackson and Dr Kate Clarke. How's the cricket series going Australia versus New Zealand? Had to get that in.

Kate Clarke: 2:19

You know the answer, Craig, or you wouldn't ask I think I'm going to give that cricket question crickets.

Craig Underhill: 2:27

All right, so let's get straight into it. Chris, I took a question on notice in the last episode. You had a question about whether no pain, no gain, whether there was importance to try and elicit in a related adverse event giving a checkpoint inhibitor. Because there's this relationship between having an adverse event and doing better in lung cancer as a paper we discussed at the last episode. So I took that on notice. I did a little bit of research and we've got a link to a paper that was called Cancer Immunotherapy Dosing a Pharmacokinetic, pharmacodynamic Perspective, and so the short answer is the no pain, no gain is not really an issue.

Craig Underhill: 3:08

It's different to chemotherapy. That's why we've evolved to going from a BSA or weight-based dosing to a fixed dose of checkpoint inhibitor and longer and longer time intervals. So there's some pharmacokinetic evidence that you get these long trough levels of the drug. We don't understand what the biomarkers are related to response that are positive predictors of response. There's some inconsistent results around PDL1, tmb. There's some intriguing clues that microbiome might be important and we're going to talk about that in this episode, but in effect, maybe that we can test patients' levels of drug and actually extend out even more the intervals of dosing and reduce the cost to the medical community and the taxpayers, but we don't need to increase the dose to try and elicit a response. There's no relationship between the dosing and the likelihood of an adverse event.

Christopher Jackson: 4:09

Yeah, it's a really interesting question around the dosing of immune checkpoint inhibitors, isn't it? I think that when we did Pembolism-Ed studies initially we were looking at two versus 10 milligrams per kg, for example, in two weeks or three weeks, and for example, there was certainly a dose response in terms of the PFAS, curves did track slightly above the higher dose than the lower dose. We didn't relate that to adverse events particularly, but we didn't really establish what a minimum effective dose was for that. And there was that fantastic study in India that was reported at ESCO last year, I think it was, which showed that 20 mgs of volume was enough. And the other way I've got around the dosing studies.

Christopher Jackson: 4:46

A couple of things, to start, as New Zealand, we started off with a 2mg per kg Pembolism-Ed. Then they got on no fixed dose, 200. But actually there's a whole bunch of patients who are under 100 kgs, who would actually get under 200 milligrams, and they changed the vial size to 100 milligrams. You have to dose everyone at that level. You can't underdose anyone at 2mg per kg anymore, so it ends up costing the taxpayer more money on the whole around there. And then the dosing intervals are all done off pharmacokinetic studies rather than actually off efficacy studies, and so it's an assumption that the pharmacokinetic modeling will translate into no difference in toxicity or no difference in efficacy. But we're accepting PK as a surrogate rather than necessarily demanding the same little clinical data. So I think there remain some uncertainties there. I'd like to see us do more dose minimization studies and more dose duration studies, but I expect that they will be academically led rather than pharmaceutical currently led Exactly.

Kate Clarke: 5:40

Do you think we need to change our whole phase one philosophy? We are still throwing a lot of drug at seeing the people and seeing if throwing more drug at people is better.

Craig Underhill: 5:48

Yeah, for immunotherapy. That may well be the case, Kate.

Kate Clarke: 5:52

And targeted therapy. You know, we know there's a differential response, for example in enrolimus. As you go from a low dose to a high dose, different things happen molecularly and maybe we're doing the wrong thing by giving people as much as they can tolerate not that many people can tolerate enrolimus.

Christopher Jackson: 6:07

Yeah, well, Kate, I think that the medical oncology approach to dosing is the same approach that we had to alcohol in first year university, and that is if some is good, then more is better.

Craig Underhill: 6:20

What do you mean? University?

Christopher Jackson: 6:25

Chris? Is that too long ago for you, Craig?

Kate Clarke: 6:26

You can call me Chuckie Craig if you like.

Craig Underhill: 6:29

So let's move along, Kate. What have you got for us this week was your long paper.

Kate Clarke: 6:35

My long paper. It's not a new paper, it was published in JC at the beginning of last year. But like most jobbing oncologists, I do most of my reading when I have a question about a particular human. And I've had a wee cohort recently of three DMMR gastric cancer patients who have all, for variety of reasons, been people I didn't want to give chemotherapy to anyway in the neoadjuvant setting and I wanted some data to back that up because we've gone from. You know, when we all started as oncologists we're all probably older than many of the list is people had surgery alone and then we went through magic and then flot.

Kate Clarke: 7:07

It is quite hard now to talk surgeons out of chemotherapy. So I wanted to see what sort of data was out there and although the particular patient I'm talking about sadly doesn't have the wherewithal to use this, but I did enjoy this phase two study looking at a combination of Ipi and Nevolumab because the outcomes are very reminiscent of niche two. So 60% pathological complete response rate and very high major response rates in patients who had some Ipi and some Nevolumab beforehand. Frustratingly, the study does have an adjuvant of volume and component to it and frustratingly, the Ipi and Nevo is about. I can't do the maths now. I think it's about three times as many doses as niche two, but with the same outcomes. So I was just I was curious. I'm waiting for some sort of phase three I'm assuming that's going to be complicated and understanding what on earth will be your comparator arm.

Craig Underhill: 7:59

You know this is a rare cancer. We haven't I can't recall one recently. Kate, we routinely test the mismatch repair gene on all colon cancer biopsies. So we but I can't remember the recent discussion about what to do in the neo-adjuvant space. So this is complicated because of the difficulty accessing the drug. I think to your point about phase three. I think there's going to be really hard to do right because the data is so compelling and we talked about it a little bit in the last episode.

Kate Clarke: 8:26

I think, Craig, I'd like to move it up a bit because I think the the lowest stuff I think is now standard of care. So rectal colon people will discuss MMR appropriate strategies. But I think this is interesting because this is gastric cancer, so different cohort of patients but very similar outcomes to niche two, craig and Chris, what do you do for upper GI and DMMR early cancers?

Craig Underhill: 8:47

In the absence of a trial, Kate, I think it's a really hard discussion because we don't have great data. I mean, if a patient can afford to pay, obviously it's a discussion you would have in the data. Is that we shouldn't make judgments about that. We should probably leave that up to the patient to decide about the ability to pay or not. But I think in the absence of a trial is quite difficult. Chris, are you able to access drug for these patients or study?

Christopher Jackson: 9:16

Well, not presently. I don't see that much DMMR gastric, a whole lot less than you would think from the numbers that you would predict. With Lynch we certainly see an awful lot, particularly BRAF, mutant colon cancer, with DMMR. That's pretty common in my world, dmmr upper GI much, much, much less common. I think. More than the IO data being persuasive, I think what's interesting is that the chemo resistance data is dissuading. The retrospective analyses from MAGIC, for example, really show that the DMMR patients are chemo-refractory. That, to me, is what would push me towards thinking about other ones. We don't know that so much from taxings. Of course it's more platinum fluriuricil, but I tend to think of DMMR as a relatively chemo-refractory condition.

Kate Clarke: 10:03

Yeah, I think the lack of flock data I think has left in ESMO guidelines. They've left that little wiggle room. They've said they don't know whether the taxing changes that, that they recommend no MAGIC, which is a bit frustrating because it's a bit woolly but that's where the data is. They're not telling lies. It's just it's frustrating. No, I think it's very much a watch the space. I think probably, if you think about in the stage four, all diseases seem to have. All DMMR diseases except pancreas seem to have very similar response rates and very similar control times. So I think maybe that kind of neo-adjuvant strategy is going to move into all of them. But I will keep my fingers crossed for more data.

Christopher Jackson: 10:41

Okay, what do you think increases the refractory one?

Kate Clarke: 10:44

Because it's my nemesis. No, I think, I genuinely think it's because it's so clever. It's that interaction between the cancer itself and the. It changes its whole macro and micro environment to protect itself. I was very hopeful in the High Lawn and Days stuff first came out. Then of course it wasn't born out. You know that would make a path for both chemo and cells to kill the cancer. I find pancreate cancer absolutely fascinating, but I do think it's a whole of body disease. That's different.

Christopher Jackson: 11:15

Do you hold out any hope for the AGIG? Send one study.

Kate Clarke: 11:18

Look the data that I've seen look fantastic, but you have to have hope.

Craig Underhill: 11:22

So thanks, Kate. We seem to be increasingly talking about immunotherapy on the Oncology Journal Club podcast and my long paper is another in the field, and we talked a little bit before about the kind of tantalising hints that maybe microbiome is important in predicting response to immunotherapy. And so you know we like to blow our own trumpet in OJC and this week's paper was a co-author on Nature Medicine, so that was a real honour. It was one of the first tele trials we did between the Living Newton John Cancer Centre in Melbourne and Bendigo and Aubrey Rodongo in regional Victoria In rare cancer patients. They were given immunotherapy and this is one of the papers that's evolved out of the translational work looking at gut microbiome and whether there was some patterns predicting response.

Rachael Babin: 12:19

And now we're going to hear a few snippets from Craig's interview with the first author of this paper, Dr Ashray Gunjur.

Ashray Gunjur: 12:28

One of the biospecimens that was collected from the majority of patients was a pretreatment stool sample. So that's what we used to assess the gut microbiome or in this case the fecal microbiome. So we extracted the DNA from those samples and we used something called shotgun metagenomic sequencing. So this is where it's kind of the equivalent of whole genome sequencing of the metagenomes, because there's lots of different species, lots of different genomes in that stool sample. You have a really deep understanding of the whole genomes, of what is present. And then we used some bioinformatics to not only stitch together what the bugs were at the strain level but then also map the reads to those genomes to really get pretty accurate quantifications of how much of the bug was present in each of those pretreatment stool samples. And then we could actually use it to predict response or progression across these very, very different cancer types. Because we had that information in follow up and what we found was when we use the strain level information, we actually saw an improvement in the predictive performance when we cross validated across this very diverse rare cancers cohort. Then when we use them all conventional species or genus level information. So I think it to us really affirmed that hypothesis that having a higher resolution, higher granularity of the microbiome does actually make an improvement.

Ashray Gunjur: 14:00

And we found another interesting thing. We found that the signature from the rare cancers trial, where all patients are treated with epinevo, so NTC2A4, ntpd1, seem to only perform well on external cohorts where the patients had received epinevo, so NTC2A4, ntpd1. So it didn't seem to perform very well. In fact it performed like a coin toss when we tested on patients who just received NTPD1 monotherapy. And this was a little bit surprising because we always thought of NTPD1 as kind of the workhorse it's carrying, the combination of mean checkpoint blockade efficacy.

Ashray Gunjur: 14:41

But, I guess when we thought more about it it seemed like there was already evidence that the mechanism of action of combination NTPD1, ntc2a4 was quite different and that the addition of NTC2A4 probably does make a difference, especially in the interaction with the gut microbiome. There's evidence that it can change the permeability of the gut. Obviously, colitis is a much bigger phenomenon with NTC2A4. In addition, and there was evidence from other sources of data, like immunotranscriptomic data, that the immune responses were quite different to this treatment. So it suggests to us that there is a common signature of response to immune checkpoint blockade across cancer types but there might be different microbial signatures to different regimens, which we thought was interesting and we wanted to share.

Craig Underhill: 15:34

So, in summary, I think it's really important information so that signature of response is predicated on the treatment regime and rather than cancer type, which is the conclusion in the paper, and so it serves an important knowledge base for further trials looking at microbiome diagnostics or any interventions.

Rachael Babin: 15:54

If you'd like to hear more, listen to the full interview in the OJC meets Ashray Gunjur episode, which you can find on our website, youtube, and on streaming apps. Now back to the team to hear what they think about this paper.

Craig Underhill: 16:10

I hope you enjoyed that interview, chris and Kate. Ashwary is an incredibly impressive young clinician researcher currently in Cambridge. We hope that you'll come back to Australia one day. What did you think?

Kate Clarke: 16:23

I think microbiome should be thought of as a whole other organ and we ignore it at our peril, both in terms of developing cancers, protecting us from cancers and obviously influencing our response to therapy. I am fascinated by the transplant of one microbiome into another person. Responders and non-responders Absolutely incredible. Hopefully some sort of clinical application in the future. More gastroenterologists running around with fecal slurries to give to people. I have a very skinny husband who's always teasing me that he could donate me his microbiome and I would lose some weight without any effort. I absolutely fascinating to blow a New Zealanders trumpet. There's Dr Ractual Purcell as a scientist in University of Otago who's doing some really interesting work about the microbiome and colon cancer. Again, I think you ignore the microbiome at your peril, chris.

Christopher Jackson: 17:11

I just wonder if we should get gastroenterologists to run around without cleaning their cologne scopes.

Kate Clarke: 17:16

But you don't want to get a fat, unhealthy person before you in the list Cece. You want a skinny, attractive person.

Christopher Jackson: 17:23

Yeah, well, I think that the microbiome data is all starting to come together, isn't it? We know that the impact of antibiotics has a negative effect on immune checkpoint inhibitor, which clearly is going to be mediated by the gut. The potential impact of PPI, for example, on the efficacy of PD1 inhibitors, particularly melanoma, from observational data seems to be pretty interesting, and again, that would logically be done via the impacts on the gut also. Look, I think the microbiome is fascinating. I don't understand these guys and how they study it, and I would have thought that the microbiome and the ascending colognes, different from the descending colognes, different from the rectum, different from the small intestine, and actually how you can study that and understand where in the cologne it's impactful. It's interesting because all the stuff was done from fecal samples, right, so the fecal sample won't necessarily reflect what the microbiome is doing in the upper gut level and where it is. It's important, I think.

Craig Underhill: 18:15

You know you comment that we've got evidence about PPI and giving antibiotics before. I think it's not that clear cut. You know we could do a whole episode about microbiome and cancer, I think.

Christopher Jackson: 18:27

I agree that it's not a slim dunk and there seems to be class impacts of the antibiotics, right. But I think it's data which you look at, which you can see an association between the impact of antibiotics and the response, which is observational, which is clearly pre-hypothesis testing. But it's interesting and the pathway by which it would act would clearly be the microbiome one. The other thing I really liked about that study too, craig, was how you know, you took the microbiome from the patient and transplanted it to the mouse and then you tested the efficacy of the PD1 agent and it mirrored the response in the patient.

Christopher Jackson: 19:00

Now that also is another emerging area that people are interested in with organoids, for example, when trying to test chemotherapy sensitivity or translocating tumor into mice and testing chemotherapy sensitivity in that way. So that's the ultimate way you can do personalized medicine. Unfortunately, it doesn't predict for toxicity. It might do for efficacy, but as a patient it's so attractive. Can you please test my tumor for effectiveness of the schema therapy panel or the immunotherapy panel and having an animal model to check what later lines of therapy might actually be most useful?

Craig Underhill: 19:28

Good discussion, Chris. What have you got for us today?

Christopher Jackson: 19:31

Well, at the end of last year we did a review of the total neurodivine therapy and rectal cancer papers and we've just had the five year update of the OPRA OPRA paper published in JCO. And OPRA was a randomized phase two study which looked at the sequencing of chemo-radiotherapy or chemotherapy in patients with locally advanced rectal cancer stage two or stage three. So these were patients who predominantly had tumors within six centimeters of the anal verge who were randomized to receive either radiation first standard long course with capsidobenol5FU, followed by FP-Ox, fluoroprime and oxyloplatin, either KEPOX or FALFOX, for 15 or 16 weeks, versus a reverse sequence of 16 or 15 weeks of induction chemotherapy followed by radiation. So we've got chemo first or radiation first as the approach. And the OPRA study was looking at disease-free survival. It was primarily an organ-preserving study that was looking to see how you could get on with preserving the rectum if you could avoid having a stomach. That's why the lower third rectum patients were particularly the ones who were interested here. There was no comparator arm of chemo-radiotherapy only or chemo only or surgery only, so it's only comparing the strategy there.

Christopher Jackson: 20:45

Now OPRA has been around for a while and people will know the results that chemo-radiotherapy first, so radiation first, followed by consolidation. Chemo was better in terms of TME-free survival, so organ preservation basically and it showed that the five-year TME-free survival was about 15 odd percent better with radiotherapy first. So you're more likely to keep your rectum if you had a stage two, so T3, t4, or a stage three, so TNE-N1, n2, if you had the chemo-radiotherapy first. In the original publication the local relapse was equivalent between the two arms and the five-year disease-free survival was equivalent between the two arms. What the update, the five-year update, has shown is that TFS remains the same. Overall survival is within 3 percent slight favoring for chemo first, 3 percent higher non-slip event. And the five-year TME-free survival was better with radiation first, 54 percent versus 39 percent with chemo first. So again confirms that headline result If you go radiation first you get a 15 percent 15, higher rate of TME-free survival. So half the patients who have this strategy can preserve their rectum and end up with no operation and without even a temporary stoma.

Christopher Jackson: 22:00

One of the interesting things about this paper was the local regional free survival data. Now what I remember back to repeat, which was the short course followed by chemo paper, where the local regional failure was worse and the experimental arm was short course followed by chemo. Now it was 4 percent worse in the short course followed by chemo and what the authors hypothesized was that the extra long duration between radiation and surgery led to those who had radio-resistant clones forming a higher likelihood to have local recurrence. And the chat that I'd heard was that repeat people went off it because of the 4 percent higher rate of local regional failure and so most people were going prodigy or opera instead of repeat-o.

Christopher Jackson: 22:51

In the five-year update of Oprah the local regional free survival actually had exactly the same difference. So 4% worse local regional failure in the radiation first arm. So chemo first, followed by chemo radiation, had lower rates of local regional failure than radiation first. So again, if you have your radiation followed by long course of chemo, you've got higher local recurrence than if you have the reverse sequence 4%, and I don't think that's been fully digested yet. So I think that that 4% worse local recurrence seen in Oprah, same extent as seen in Repito, needs to be thought about quite carefully. I think there's a general bias towards long course chemo-radiotherapy in general against short course. But actually with the massive increases in demand for radiation which we predicted over the next 15 years, we have to be really thoughtful about our resource use and minimizing fractionation schedules, minimizing exposure where we can, in order that we can free up capacity on these machines, and so we have to fully digest the implications of that difference when we're thinking about this strategy.

Craig Underhill: 24:03

So interesting paper, chris. So just to clarify. So this was all the patients reset, had long course Chemo therapy, chemo-radiotherapy and then either watch your weight or immediate TME. Half the patients didn't need on the watch or might didn't need to have surgery, which is fantastic. You alluded to the short course, so has there actually been a direct comparison between neo-adjuvant short course chemotherapy versus the long?

Christopher Jackson: 24:27

So not in the TNT setting. The short versus long was of course an excellent drug study, so Australasian study.

Craig Underhill: 24:36

Yeah, but in this neo-adjuvant approach and then a watch and weight, have we got a comparisons? Because of those resource implications and the fact that with this approach that you just talked about, where the long course we're committing it's quite a big resource allocation but you could hypothesize that the long course higher dose of radiotherapy for longer might be important in achieving that 50% long term local control.

Christopher Jackson: 25:02

Yeah, I think what the Oprah study shows us is that long course, with a long weight within section of chemotherapy, results in better organ preservation, but it doesn't result in better local control. So you have to be very clear about what your goal is. Is your goal to preserve local control or is your goal to avoid a stoma and have organ preservation? And so I think having clear conversations with patients about what your goals are is it local control? Is organ preservation? Is it? Doesn't metastasis free survival? What is the main goal of your therapy?

Christopher Jackson: 25:36

Which makes this conversation about how you best approach neo-adjuvant therapy and rectal cancer so much harder than it's ever been before, and I love the fact that we've actually got so many more options to discuss with our patients. We've discussed previously on this podcast the Prospect study, which was the chemo with selective radiation therapy, and whilst again, that was a non-comparative study in terms of included patients who had more favourable characteristics than either Pradesh or Oprah, for example, but what it showed us is that those patients who have had previous pulveridia therapy could have chemo instead. So I think this is a complicated area. Now we've got more options, we're having more complicated discussions with patients, more complicated discussions with surgeons. What's becoming increasingly clear is that for those who are T3, t4 or stage 2, we're no positive. It should be getting some form of neo-adjuvant therapy now. Surgery alone is probably not a standard of care anymore in those intermediate patients and that you can have the option of stoma-free survival and organ preservation in up to half the patients on stage 2 or 3 cancers in that lower through.

Craig Underhill: 26:34

Yeah, what do you think, Kate? I think it's hard to have this conversation with patients. It's confusing. It's confusing for surgeons and medical oncologists and radiation oncologists. You know people misquote stuff in their MDTs.

Kate Clarke: 26:46

I actually think this now in my region we have ENT combined clerks, we have gynecobind clinics, so that patient only hears the one story after everybody's had their chance to have an argument and we're taking the patient's voice into account. I think this is something that lends itself to a patient having a proper staging and an MDT discussion before they're presented with the options that are medically possible and then they can help make a choice based on their own priorities. Otherwise you a little bit like the prostate cancer, you know, we know that a patient with prostate cancer meets a surgeon, they get an operation. If they meet a radiation oncologist, they may choose not to have an operation. So I really think that rectal cancer is something we need to do as a team.

Kate Clarke: 27:26

It is really hard, the conversations with patients you know that's what Medox are good at but I think the way through the data of figuring out what's the right course for which course, I think that's getting really tricky Because some of the questions we're asking haven't actually been answered. You know, compare this with compare that Nobody's done that. They've moved things around and of course every single trial has a different population in it. So it's very hard to make those decisions or even think about what the appropriate option is for each patient.

Christopher Jackson: 27:53

Kate, you know resourcing, particularly radiology, is a really vexing issue in the New Zealand context. What's been your experience with accessing watch and wait because of radiology restrictions?

Kate Clarke: 28:03

So actually we were having this conversation locally because we're going to end up for the first time. I think the surgeons are experiencing the difference between private and public care and cancer surgery. So we can do excellent TME surgery in either sector with no real weight. So whenever we want it sorted, no problem. We cannot do four MRIs a year and four surgical outpatient appointments a year in public, so the private patients are being presented with the option of watching waits, the public patients. It's really not an option we can honestly do in a quality controlled fashion, because we can't resource the MRIs, and that is something that I think the surgeons. You know we're used to having unfunded conversations all the time, but I don't think that's something surgeons are at all comfortable with, and so it's on our agenda to have a chat about whether we can figure out how many people it really is and what kind of resource it would need, and whether we can make it happen.

Christopher Jackson: 28:53

So, kate, I think New Zealand medical oncology has been the buttermenia joke in terms of our lack of availability of medicines. But what that has done also is it's sharpened our thinking about resource allocation and prioritization. We've had long waiting lists, for a few days, for example, and it makes us think about bang for our buck in terms of how we prioritise access, and resource constraint in oncology is a realistic problem, and I think that the rest of the world is going to face that over the course of the next 15 years, when the number of cancer diagnoses go up by 50%. In that period of time, when we don't have enough investment in linear accelerators in the public sector, where we don't have enough surgeons we're training, we don't have enough medical oncologists. We are going to have to be people who are into demand management, and the current approach in oncology of treatment intensification needs to go in the other direction, which is treatment de intensification whilst maintaining efficacy, minimising contact with healthcare professionals and minimising toxicity.

Kate Clarke: 29:43

I don't at all disagree, chris. I would need a statistician to explain to me why any treatment minimisation has to be done via a non-inferiority trial, which is almost impossible to prove. So I need somebody to explain to me why, because I think that's a real problem in our data. Whenever we try and take something away, we have to do it via a non-inferiority trial and then it can never be proven because of the nature of those rare trials.

Craig Underhill: 30:05

I'm going to play the devil's advocate. So I think we should be advocating for the best possible treatment for the patient, and then it's up to the discussion about restriction on access and fundings, except for kind of things. So that's what I think our focus should be in putting forward options, not predicate it with resource limitation.

Christopher Jackson: 30:23

So, look, I think that's a really, really good point, Craig. I live in a town of 150,000 people and when I go to the supermarket, people who are on the waiting list see me and I get phone calls and people call me and they ask to be pushed up the waiting list. So I'm managing that waiting list personally, individually for the patient. So the patients who I'm not seeing are very much as much my patients as the ones who I am seeing. So when you talk about treatment intensification and advocating for the patient in front of you, I'm also dealing with the people who are on my waiting list who I'm not currently seeing and they are also my responsibility. So when you say the patient is your responsibility, actually in my opinion, the community is my responsibility and actually looking at how I best make the needs of the entire community and deliver services for them as part of my job, I think we should be advocating for de-intensification if necessary, and that's, you know, through trials.

Craig Underhill: 31:19

We've had some Twitter discussion about that, but I think the number one job in MDT is to come up with the ideal options that you can then go away and discuss with the patient. I don't think you should predicate that with oh, we're not going to be able to do that, wait and watch because we haven't got x-ray time. Do you know what I mean? Yeah, no, I really agree with that, Craig. Then we need to be advocating with the funders as to why that's. We need to find the resources to do that. So I don't think we should be cutting corners for the sake of just rolling over and saying, oh, we've got to cut corners.

Kate Clarke: 31:50

That's really a nuance, though, craig. So I think, yes, you can have an MDT conversation where you say this is what we'd like to do for this patient. And if you think about well, for example, you know so we had recently a DMMR colon patient I knew exactly what we wanted to do for that patient, so we wanted to do niche two. That is not available in the public sector. I had to go and approach the patient with these are your options, one of which is an unfunded option. Here's the pluses and minuses of each option.

Kate Clarke: 32:18

He went away with his family, they thought for 10 days, they found the 35 grand and they came back. Those are the kinds of conversations that we will all be having here, and the sad part is, yes, we do have to come up with a genius, you know best possible plan, but we have to then present it to the patient in a way that is understanding of what they're actually going to be able to get, but also respectful of the fact that if it is something that they're going to have to come up with money for that, we shouldn't be making any judgments about what patients value and what they might have the ability to fund. But you can have both things going on at once.

Craig Underhill: 32:51

Yeah, that's right. The literature will tell us that we shouldn't pre-judge ability. They want to know what the options are, and then they will decide.

Christopher Jackson: 33:00

And I also strongly agree with you, craig, that we shouldn't be rationing at an individual level, so clinicians shouldn't be saying, well, this is a cheaper treatment, therefore, I'll do this for this particular patient here. But I think that responsibility on us, as oncologists to our researchers and who are oncologists, to our decision-makers, is looking to influence the research strategies that we employ, to focus on not only thinking about best possible treatments, the most intensive treatment, but also having a very keen eye on the resource implications of the types of research we do, the types of research questions we ask, the structure of the studies that we do, and thinking about the impacts of that resource consumption on the patients who are waiting to be seen.

Craig Underhill: 33:42

Yeah. So, kate, I think your idea about the combined clinics a great one. There's the next Health Services Research grant, if it's not already being done, but I think that's a really good idea that exploring that model and evaluating it, co-designing it with consumers, including First Nations people, so we maybe can write a grant application together.

Christopher Jackson: 34:03

Craig, have you ever seen a combined clinic done via telehealth or telebidsom?

Craig Underhill: 34:07

No, I've seen MDTs, but not that kind of arrangement, so that's a good one.

Christopher Jackson: 34:12

Would that be something that would work? Do you think or not?

Craig Underhill: 34:14

To do. Yeah, potentially might be able to be done in the public sector where people are paid. In the private sector, when there's no item numbers to do, that, might be more difficult, but it's a good thought. So moving right along. Kate, can you tell us about your quick bites?

Kate Clarke: 34:32

Yeah, so these are very quick bites. The first one is just can I get everybody to read the paper please? So it's in ESMO Open, which means it's available to everyone, and it's looking at sexual health and breast cancer survivors. The rates of lack of sexual enjoyment and decrease in sexual function is 80% 90%, and there are lots of practical things that women and their carers and their loved ones can do to improve their outcomes and they're not tricky. The most important thing that I practice in my own practice of these patients not my own practice of the other thing is to talk about it, Because I think if you actively ask your breast cancer survivors how sex is going, they will tell you. And it's not just menopause. There's a lot of other stuff going on, including the fact that we borrow these women's bodies for a year. So please read the paper and have a think about how you can improve this, Something that's just so very important in people's lives.

Craig Underhill: 35:27

But isn't that a question we should be asking, although patients are sure it's a particular issue in breast cancer with all the hormone changes, et cetera, estrogen withdrawal rule. But now that you said that, or thinking on something, we probably should ask people what we don't necessarily. Maybe the nurses do, but the doctors don't.

Kate Clarke: 35:45

Yeah, I worked with a great gynecogen who he was blunt but he used to talk about the three S's, which was sitting, shitting and sex, and although that was facetious, it is actually quite helpful for your post-gyne cancer survival, particularly with radiotherapy, palpacists and things. So I think we need to talk about it more and perhaps school ourselves up in how to have those conversations, but also what tools are out there to help women and I'm sure men can do with some help too.

Christopher Jackson: 36:11

Cancer, obviously, is a median age of people in the mid-60s. We don't want to think about people of our parents' generation having sex, but of course, it's a really important element of people's overall happiness and life contentment, isn't it, and that's part of patient-centered medicine. I think it's a big conversation, though, kate, and it's a difficult conversation to have in a compressed outpatient appointment. It's one of those things that you easily dropped off the agenda of the many things that we have to do in a compressed outpatient's appointment.

Craig Underhill: 36:35

Chris, 60s is not my parents' generation. But anyway, great paper, kate. We'll just move along. Thanks for pointing that out. Everyone should read that Isma open. And then your second one.

Kate Clarke: 36:47

No, my second one is actually apropo, after we've been talking about microbiome, because of course, microbiome includes pathogens, and it is about four papers, but this is one of them connecting H pylori with colorectal cancer. It may well be an indicator of poor health access or poverty, but there is definitely an increase in incidents and in mortality from colorectal cancer in those patients with H pylori, particularly untreated H pylori. So don't think about your microbiome at your peril. Keep saying that. I think there's so much more in that we live with a whole community of creatures, some of whom have not got our best interests at heart.

Craig Underhill: 37:24

So, kate, is the implication of that, and then if we have a patient with colon cancer, we should do a breath test and then treat H pylori. We've got strong evidence of intervening.

Kate Clarke: 37:34

That's as epidemiological. And there's lies, damn lies and epidemiology. But I think there's about four different papers with four different groups of researchers. So I think that's coming. I would like to, if we go back a step in terms of quality, could you, hand on heart, say you're doing that for every gastric cancer patient at the moment? Ismo checklists have just come out and some cancers and I look at them and think, god, I'm sure I'm doing everything on that list. I'm sure I'm not. So I think, in terms of quality, maybe we hit the one where we know it matters first, and this is in the two we announced.

Christopher Jackson: 38:02

Kate, with epidemiological studies, that's clearly a life course risk factor. Is there anything that you could read in that paper around critical periods of exposure to H pylori in terms of where it might be important that you're exposed to that in your development?

Kate Clarke: 38:15

No, that was a large age group. It's a 15-year time difference, so I don't think that they're able to say are you looking at? Why are we getting so many young people with colocanthin?

Christopher Jackson: 38:25

If you look at the epidemiology of GI cancer in general, you see the incidence dropping in elderly but going up in the youngsters and the incidence change is in keeping with infectious disease.

Christopher Jackson: 38:37

It's not in keeping with a found or a fetrogenomic influence, it's environmental exposure, of which impact on the microbiome again seems most likely to be, whether that's dietary or antibiotic usage or whatever. It's fascinating Again, you mentioned earlier our colleague Dr Ritch Purcell from Christchurch who did a stool sample on patients from the Christchurch cohort who found back droid is fragilis, again was associated with a higher rate of bowel cancer instance usual. And again you've now presented the paper on H pylori and, Craig, you've got the paper today on the whole genome signature as to how that might impact on incidence. It's interesting to know what state in your life course that's important. It's interesting to know what impact, as you say, Kate, is to do with confounding and how much of that's overcrowding, poverty, diet exposures that are also correlated with those bacteria to give you that risk. But what's clear is that we need to understand it better and look at what interventions are going to make a difference.

Kate Clarke: 39:33

I think that the early onset colorectal cancer stuff is frankly terrifying. I'm preparing a check for some radiation oncologists tomorrow and the talk is breast cancer and pregnancy. But when I look through my cases, I've got one but I've got three women with colorectal cancer and pregnancy. That wouldn't have been what I would have guessed when I had a thought of what I would draw through. So I think we've got a lot of work to do in that space, not only to treat these people properly. And obviously, despite Chris's attempt at being non-age biased, the sexual function in 20 and 30 year olds is perhaps more of a concern, but these people have lifelong toxicities ahead of them. So it would be lovely to not be looking at total neurodegenerative therapy in 25 year olds Great.

Craig Underhill: 40:10

Thank you, good discussion. So I've got a couple of quick bites and so I picked these on the basis of them being potentially answering kind of real everyday questions, one in GI cancer and one in lung cancer. The first one is a paper by Sunner or in general oncology association between duration of immunotherapy and overall survival in advanced non small cell lung cancer. So we've known in the past there was a randomized study stopping after a year of immunotherapy you can see the New Zealanders eyes are glazing over giving immunotherapy lung cancer. So randomized, just stopping after a year and patients who stopped early didn't seem to do as well and didn't necessarily respond on being re-challenged with immunotherapy. This is a retrospective study, large series looking at the question of stopping after two years and it appeared to be minimal difference between the two groups. So some prospective studies specified two years of immunotherapy and then stopping. Others continue with the immunotherapy, which obviously has big cost implications for the system. So again, this is a retrospective study but it appears to show minimal difference. So it does give summary assurance to having a discussion with patients at two years about whether you can discontinue their checkpoint inhibitor. But I think the definitive randomized trial probably needs to be done and the second one is in re-challenge after oxaliplatin induced hypersensitivity reactions Again in general oncology.

Craig Underhill: 41:40

It was a letter to the editor from French medical oncologist Rassie at all, and this is the largest reported series to date of re-challenging people who've had a hypersensitivity reaction to oxaliplatin. In the past we've tended to probably someone's had a reaction. We just go okay, well, we're going to. You know, we pre-medicate them next time they had another reaction, then we just stop it and there's been some re-challenged protocols around. So this is the largest series to date. But patients are given more extensive pre-medication there, kept as an inpatient, given very slow infusions, and the vast majority of them were able to get through without having a repeat reaction. And if they did have a repeat reaction, no one died or ended up in ICU or had an anaphylaxis. So that's kind of reassuring. So Chris and I had some chat on WhatsApp about a case. So, chris, in your practice do you very often re-challenge these patients who've had an oxaliplatin induced hypersensitivity reaction?

Christopher Jackson: 42:41

I think one of the interesting things that came out of the discussion around this on our WhatsApp group, Craig, was the fact that because New Zealand has fewer options, we end up re-challenging patients with previous agents not infrequently, and I think that we've known for some time that when you re-challenge someone with cisplatin or carboplatin the rates of hypersensitivity go up and the gyne guys are quite used to doing desensitization. Perhaps in GI cancer we don't do that as much because people have had neuropathy, but in New Zealand, where you've got a limited range of options, you tend to re-challenge people when you're getting to third or fourth-line therapy. So we do that a lot and I see a remarkable amount of hypersensitivity to oxaliplatin on the second, third, fourth infusion of re-challenge. We've had really good experiences with desensitization and we've managed to get most of our patients to have the agent reintroduced using a protocol, one in particular who has had NFLX. It's proper NFLX, it's not hypersensitivity. I think it would take a very courageous clinician to re-challenge them and I'm not brave enough quite to do that yet.

Craig Underhill: 43:39

Okay. So, chris, do you have some short bites for us?

Christopher Jackson: 43:43

Yeah, well, here is the news. First of all, new Zealand's parliament has voted to reverse several important pieces of legislation which impact on cancer rates in the New Zealand environment. The last week we've seen the new coalition government reverse New Zealand's world-leading smoke-free legislation. So the smoke-free legislation in New Zealand was designed to have an inverse-sinking lid by raising the age at which you would be able to buy tobacco, so 18, then 19, then 20, then 21. To be a whole generation of kids, those born in 2009 or after would never be able to buy smoke tobacco. They would reduce the number of tobacco outlets from something like 600 to 60, I think, so quite a small number of tobacco outlets to make tobacco more difficult to get, and would de-nicotine-ize cigarettes. They'd take the nicotine out, so 5% of current nicotine levels in cigarettes in order to get a truly smoke-free generation.

Christopher Jackson: 44:35

New Zealand's making good progress in smoke-free in general, with fewer than 6% or 7% of New Zealanders smoking daily. But there's still stark ethnic inequalities, with Māori Pacifica more likely to smoke around about 17 to 20%, I think the latest numbers are and so removing this legislation will have a disparate impact on those indigenous communities. The legislation reversal has been met with derision by the wider medical community. There are libertarians and tribalists who've tried to defend the legislation reversal. But it's also a shame to see some in-game tobacco legislation reversed which could have been a blueprint for the rest of the world. The tobacco lobby is alive and well and underestimated at your peril.

Craig Underhill: 45:20

Yeah, thanks, chris, there are no words really. And watch a second bit of cheery good news.

Christopher Jackson: 45:27

In New Zealand we had the Māori Health Authority whose sole goal was to reduce ethnic inequalities and outcomes for health. Of course we have stark ethnic inequalities and cancer outcomes, with Māori 20% more likely to be cancer and twice as likely to die from cancer, and a variety of other ethnic inequalities and cardiovascular disease, infectious disease, diabetes, etc. The Māori Health Authority was a by Māori for Māori commissioning agency who's designed to work with local agencies in order to commission local services to get services to local communities. Now you can't get away from the social determinants of health, but still access to health care is critical for these communities. The Māori Health Authority has been going for just over a year and unfortunately again the coalition government has disestablished this again world-leading indigenous commissioning body before it's had chance to establish its feet and to have chance to have an impact. So that's again been a sad day. That's going to be incorporated in our Ministry of Health. That will mean that the Māori Health Authority will report to the ministry. So perhaps no net loss of investment, but certainly a major difference in autonomy and independence of that group. So it's a shame it never got off the ground properly.

Christopher Jackson: 46:36

My quick bites this week are Alanzapine 2.5 vs 10mg to prevent chemotherapy-induced nausea and vomiting. The single-centre open-label randomized phase 3 non-inferiority trial conducted at Tata in Mumbai looked at patients receiving AC or cisplatin greater than 70 m2, who got standard antibiotic prophylaxis with dexamethasone, a prepotent, and 5-HT3 antagonists. And patients got either Alanzapine high dose, 10mg or 2.5mg and bottom line is no difference in the rates of complete control of nausea or vomiting, but less sedation Whenever we're already using 5mg. Now I think the study gives us confidence to use 2.5 and to get away from the sedation impact. Great study, super cheat practice changing in my opinion. Let's lower the dose of Alanzapine.

Christopher Jackson: 47:20

Another great study which was in JCO just this last month was a review of the E191-2 trial, which was a CLL study of our Bruton v FCR. But the interesting thing about this study was that it looked at the importance of grade 1 or 2 adverse events and treatment discontinuation rates and what it found is, as you had grade 1 or 2 adverse events, so if you had grade 1 adverse events, you had a 13% increased likelihood of discontinuing your chemo. If you had a grade 2 adverse event, you had a 35% likelihood of discontinuing your chemotherapy. So next time you hear an ESCO plenary discussant or speaker saying this treatment was well tolerated and had manageable toxicities. Think about the grade 1-2 side effects and what that might do to discontinuation and therefore what that might do to efficacy. These grade 1-2 toxicities, they matter. Patient experience matters.

Craig Underhill: 48:09

Great. Thank you, it's great. No, it's so much to talk about, it's fantastic. Thanks again, kate and Chris and Rachel on the sound desk there. Thanks to all the listeners. Thank you for sending all the positive feedback. Keep it coming and have particular papers you want to suggest to us. Please send them in. And thanks again, everybody.

Rachael Babin: 48:32

You've been listening to the Oncology Journal Club podcast, proudly produced by the Oncology podcast, part of the Oncology Network. For regular news and podcast updates, we invite healthcare professionals to join us at oncologynetworkcomau. Your free registration includes a free subscription to our weekly publication, the Oncology newsletter, and it's a fantastic way to support the OJC. And don't forget to shout out any feedback or paper recommendations to us via our socials. This is Rachel Babin and this is the Oncology Journal Club podcast.